A native of Charleston, South Carolina, which is also the setting of her novels Dreams of Sleep, Rich in Love and The Fireman's Fair, Humphreys was educated at Ashley Hall (Class of 1963), studied creative writing with Reynolds Price at Duke University (A.B., 1967), and went on to attend Yale University (M.A., 1968) and the University of Texas. She held fellowships from the Woodrow Wilson Foundation and the Danforth Foundation. From 1970 to 1977, before beginning her writing career, she taught English in Charleston.

While her first three novels are mainly about contemporary family life in the South, her fourth, Nowhere Else on Earth, is a departure in that it is an historical novel based on the true story of Rhoda Strong and Henry Berry Lowrie from the American Civil War era. It won the Southern Book Award in 2001.

Rich in Love, probably her best-known novel, was made into a 1993 film of the same title directed by Bruce Beresford, from a screenplay by Alfred Uhry, starring Albert Finney and Jill Clayburgh.

Humphreys was the winner of the 1984 Hemingway Foundation/PEN Award, for Dreams of Sleep, and the recipient of a Guggenheim Fellowship, the Lyndhurst Prize, and the American Academy of Arts and Letters Award in Literature.